DESCRIPTION (provided by candidate): The ability to generate potent mucosal cellular immune responses is an important goal of vaccine development. Mucosal immunity may be particularly critical in the setting of HIV infection, not only because transmission generally occurs at mucosal surfaces but because CD4+ T-lymphocytes in the intestinal mucosa are targeted preferentially for destruction early in the course of disease. However, the specific properties of a vaccine required to generate potent mucosal cellular immunity are not known. A better understanding is needed of the molecular mechanisms by which the lymphocyte priming milieu and mucosal microenvironments shape vaccine-elicited mucosal cellular immune responses. We hypothesize that vaccine-elicited cellular immune memory at mucosal surfaces is shaped both by the anatomic and molecular properties of the initial priming milieu and subsequent signals from mucosal microenvironments that dynamically reprogram T-lymphocyte homing specificity and phenotype. We propose to test this hypothesis with the following three Specific Aims: 1. To determine the key anatomic and molecular events that confer mucosal homing capacity on CD8+ T-lymphocytes following systemic vaccination;2. To assess how systemic and mucosal microenvironments impact the differentiation of vaccine-activated CD8+ T-lymphocytes;3. To evaluate the ability of mucosal dendritic cells and retinoic acid to reprogram the homing specificity of vaccine-elicited CD8+ T-lymphocytes. RELEVANCE: HIV infects over 40 million individuals worldwide. According to recent World Health Organization estimates, over 2 million people become infected with HIV each year and a similar number die from complications of AIDS. Therefore, a prophylactic HIV vaccine is urgently needed. Because HIV transmission generally occurs at mucosal surfaces and the virus preferentially targets mucosal CD4+ T- lymphocytes for destruction, a vaccine that generates effective mucosal immunity is highly desirable.